New, potent P1/P2-morpholinone-based HIV-protease inhibitors |
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Authors: | Kazmierski Wieslaw M Furfine Eric Spaltenstein Andrew Wright Lois L |
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Institution: | GlaxoSmithKline, MV CEDD, Five Moore Drive, Research Triangle Park, NC 27709, USA. wieslaw.m.kazmierski@gsk.com |
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Abstract: | We have developed efficient synthesis of morpholinone-based cyclic mimetics of the P1/P2 portion of the HIV-1 protease inhibitor Amprenavir. This effort led to discovery of allyl- and spiro-cyclopropyl-P2-substituted inhibitors 17 and 31, both 500 times more potent than the parent inhibitor 1. These results support morpholinones as novel mimetics of the P1/P2 portion of Amprenavir and potentially of other HIV-protease inhibitors, and thus provide a novel medicinal chemistry template for optimization toward more potent and drug-like inhibitors. |
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